Studies with gene markers can help to elucidate specific genes potentially involved in interindividual differences in vulnerability to substance abuse. Studies alcoholics by some, but not all investigators, indicate that a specific form of the human dopamine D2 receptor gene, marked by an RFLP gene marker at its 3' end, could be associated with increased vulnerability to alcoholism. During this fiscal year, this laboratory has developed increasingly-strong evidence that variants of the dopamine D2 receptor gene could predispose to vulnerability to other addictive substances as well. Individuals' substance abuse diagnoses by DSMIII-R criteria, and their peak lifetime substance use assessed by a newly-validated Drug Use Survey, were correlated with TaqI A and B dopamine D2 receptor RFLP genotypes by standard methods of association. Both of these gene markers were shown to be more prevalent in caucasian polysubstance abusers than in control populations. This association appears to identify the first specific gene variant associated with drug abuse. Several other features of the DRD2 locus that could support or weigh against this hypothesis were addressed. During this year, racial differences in the frequencies of the DRD2 TaqI A and B RFLPs initially associated with substance abuse were confirmed and extended. Substantial linkage disequilibrium between these 3' and 5' TaqI RFLP markers was found. Finally, no clearcut increase in the A1 or B1 frequencies were noted in substance abusers who also were psychopathic. Behavioral pathways whereby a D2 receptor gene variant might influence substance abuse behaviors are being sought by assessing gene effects on acute psychostimulant responses, examining the specific features of addiction displayed in excess by those with the appropriate genotypes, and assessing smokers, in whom environmental influences may well be less substantial.